bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–06–15
23 papers selected by
Kateryna Shkarina, Universität Bonn
  1. Dipeptidyl Peptidase 9 in Human Leukocytes: Novel Inhibitors Induce Caspase-1- and Gasdermin-Dependent Cell Death.
  2. MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection.
  3. Editorial: Differential activation of cell death pathways in macrophages as a result of adaptation to divergent microenvironment.
  4. Redox signaling in innate immunity and inflammation: focus on macrophages and neutrophils.
  5. Hormetic elevation of taurine restrains inflammaging by deactivating the NLRP3 inflammasome.
  6. PDE10A Inhibition Disrupts Lipid Droplet Formation and Sensitizes Macrophages to Ferroptosis after LPS treatment.
  7. Discovery and structure-activity relationship studies of 3-pyridazinesulfonyl derivatives as a new class of inhibitors against NLRP3 inflammasome-dependent pyroptosis.
  8. PARP12-mediated mono-ADP-ribosylation as a checkpoint for necroptosis and apoptosis.
  9. Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection.
  10. Cell death and cancer: Metabolic interconnections.
  11. NINJ1 regulates plasma membrane fragility under mechanical strain.
  12. Cell death: Dynamics and compartmentalization of NADH and FSP1 in ferroptosis.
  13. JNK signaling coordinates epithelial cell turnover through exocytosis in Drosophila ribosomal protein mutants.
  14. The CARD14sh-BCL10-MALT1 complex regulates MAVS-mediated antiviral response in keratinocytes.
  15. Ferroptosis-related LncRNAs in diseases.
  16. Hypoxia drives progression of multiple sclerosis by enhancing the inflammasome activation in macrophages with Porphyromonas gingivalis infection.
  17. GSDMD and GSDME exhibit distinct roles in enteric coronavirus PDCoV-induced pyroptosis and inflammatory responses.
  18. NLRP3 activation promotes cGAS/STING signaling and antitumor immunity by colorectal cancer cells.
  19. Macrophage pyroptosis mediates hyperoxia-induced inflammatory lung injury in neonates.
  20. mTOR Modulates NLRP3 Inflammasome Activation via Nuclear Translocation and STAT1 Inhibition.
  21. A caspase-1-cathepsin AND-gate probe for selective imaging of inflammasome activation.
  22. SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity.
  23. Myeloid-specific TFAM deficiency drives mitochondrial DNA stress and exacerbates allergic airway inflammation.
  1. Eur J Immunol. 2025 Jun;55(6): e51526
    Dipeptidyl Peptidase 9 in Human Leukocytes: Novel Inhibitors Induce Caspase-1- and Gasdermin-Dependent Cell Death.
    Joni De Loose, Kathleen Mertens, Nicolò Filippi, Sam Corthaut, Siham Benramdane, Yani Sim, Yentl Van Rymenant, Karen Claesen, Gwendolyn Vliegen, Maya Berg, Tiphanie Gomard, Guy Caljon, Isabel Pintelon, Pieter Van Der Veken, Ingrid De Meester.
      Dipeptidyl peptidase 9 (DPP9) is an intracellular serine protease with key roles in the immune response. In human leukocytes, DPP9 interacts with caspase recruitment domain-containing protein 8 (CARD8) to form an inhibitory complex that prevents spontaneous inflammation. Inhibition or depletion of DPP9 activates CARD8 inflammasome signaling and triggers lytic cell death. Here, we examined the effects of two novel DPP9-targeting inhibitors, cpd-42 and cpd-6a, on the viability of human leukocytes. Both compounds induced dose-dependent lytic cell death in myeloid leukemia cell lines without a concurrent increase in IL-1β or IL-18 secretion. We confirmed that DPP9, caspase-1, gasdermin D (GSDMD) and gasdermin E (GSDME) contribute to the cell death observed with cpd-42 and cpd-6a. In addition, both inhibitors triggered lytic cell death in isolated human monocytes, monocyte-derived macrophages, monocyte-derived dendritic cells, and T cells, with activated T cells showing the lowest sensitivity. Examination of DPP activity revealed upregulation of DPP8/9 activity upon dendritic cell differentiation. Lastly, we found that DPP9 can localize to both the cytoplasm and the nucleus of isolated human leukocytes, warranting further evaluation of DPP9's nuclear roles.
    Keywords:  dendritic cell; dipeptidyl peptidase 9; inflammasome; monocyte; protease inhibitor
    DOI:  https://doi.org/10.1002/eji.202451526
  2. Front Cell Infect Microbiol. 2025 ;15 1602965
    MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection.
    Debashree Dass, Anwesha Banerjee, Ashwini More, Anupam Mukherjee.
       Introduction: Herpes Simplex Virus Type 2 is a prevalent sexually transmitted pathogen that causes genital herpes and severe neurological complications, including meningitis and encephalitis. A major challenge in HSV-2 infection is the uncontrolled inflammatory response mediated by NLRP3 inflammasome activation, leading to pyroptosis and excessive cytokine secretion. Despite its significant clinical burden, the molecular mechanisms underlying HSV-2-induced inflammation remain poorly understood. Recent evidence suggests that microRNAs play a crucial role in regulating host immune responses and inflammasome activation. In this study, we investigate the regulatory role of miR-141 and miR-211 in modulating inflammasome activation and viral replication during HSV-2 infection.
    Methods: THP-1-derived macrophages were transfected with miR-141 or miR-211 mimics or scrambled controls before infection with HSV-2. Quantitative PCR and Western blot analysis were performed to assess the expression of NLRP3, CASP1, IL-1β, IL-18, and GSDM-D. Luciferase reporter assays were conducted to validate miRNA-target interactions, and ELISA was used to quantify cytokine levels in culture supernatants.
    Results: Our results demonstrate that HSV-2 infection significantly downregulates miR-141 and miR-211, leading to enhanced NLRP3 inflammasome activation, increased caspase-1 cleavage, and excessive secretion of IL-1β and IL-18, ultimately causing pyroptotic cell death. Transfection with miR-141 and miR-211 mimics restored miRNA expression, resulting in a marked suppression of inflammasome activation and inflammatory cytokine release, as well as significant inhibition of HSV-2 viral gene expression. Luciferase assays confirmed that miR-141 directly targets NLRP3, while miR-211 regulates CASP1, validating their roles as post-transcriptional repressors of inflammasome components.
    Discussion: These findings establish miR-141 and miR-211 as critical modulators of HSV-2-induced inflammasome activation, highlighting a novel miRNA-based regulatory mechanism. Restoring these miRNAs significantly reduces viral replication and inflammation, underscoring their potential as therapeutic targets for managing HSV-2-induced immunopathology. Future research should focus on in vivo validation and therapeutic optimization to develop miRNA-based interventions.
    Keywords:  HSV-2; IL-1β; NLRP3 inflammasome; caspase-1; inflammation; mirna regulation; pyroptosis
    DOI:  https://doi.org/10.3389/fcimb.2025.1602965
  3. Front Immunol. 2025 ;16 1623587
    Editorial: Differential activation of cell death pathways in macrophages as a result of adaptation to divergent microenvironment.
    Krzysztof Guzik, Philippe Saas, David Masson.
      
    Keywords:  atherosclerosis; ferroptosis; inflammation; macrophage; macrophage plasticity; microenvironmental adaptation; regulated cell death; single-cell transcriptomics
    DOI:  https://doi.org/10.3389/fimmu.2025.1623587
  4. Free Radic Biol Med. 2025 Jun 06. pii: S0891-5849(25)00755-5. [Epub ahead of print]
    Redox signaling in innate immunity and inflammation: focus on macrophages and neutrophils.
    Ilana Braunstein, Hozumi Motohashi, Tobias Dallenga, Ulrich E Schaible, Moran Benhar.
      Redox signaling plays a central role in regulating macrophage and neutrophil function, integrating reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) to modulate innate immune responses. Reactive species modulate diverse cellular processes in phagocytes, including differentiation, metabolic adaptation, cytokine production, and cell death. Antioxidant systems, including the glutathione and thioredoxin systems, play essential roles in maintaining redox balance, counteracting excessive oxidants, and preserving immune cell function. Oxidative post-translational modifications of proteins, mainly on cysteine and methionine residues, act as redox switches that regulate innate immune cell function. Dynamic redox modifications critically influence phagocyte metabolism, migration, phagocytosis, survival and communication with neighboring immune and non-immune cells, thereby controlling the response to infection as well as initiation and resolution of inflammation. Additionally, other oxidized mediators, such as oxidized mitochondrial DNA and oxidized lipids, contribute to immune regulation and its dysregulation in inflammatory diseases. Thus, redox signaling is tightly linked to both immune homeostasis and pathological inflammation. This review explores the mechanistic basis of redox regulation in macrophages and neutrophils, emphasizing the interplay between ROS, RNS, RSS and antioxidant defenses. We also discuss recent insights into the role of redox regulation in the context of pulmonary infection and inflammation. Overall, a deeper understanding of these redox-regulated pathways may reveal novel strategies for selectively modulating inflammation while preserving essential immune functions.
    Keywords:  Redox regulation; infection; inflammation; macrophages; neutrophils; pulmonary disease
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.006
  5. bioRxiv. 2025 May 31. pii: 2025.05.27.656381. [Epub ahead of print]
    Hormetic elevation of taurine restrains inflammaging by deactivating the NLRP3 inflammasome.
    Chenyang Guan, Seungjin Ryu, Mingze Dong, Yun-Hee Youm, Subhasis Mohanty, Rae Maeda, Lucie Orliaguet, Hee-Hoon Kim, Tamara Dlugos, Steven R Smith, Eric Ravussin, Janset Onyuru, Andrew Wang, Albert C Shaw, Hal M Hoffman, Yuval Kluger, Yuki Sugiura, Vishwa Deep Dixit.
      Taurine, the most abundant sulfonic amino acid in humans is largely obtained from diets rich in animal proteins. However, taurine is dietary non-essential because it can be synthesized from cysteine by activation of transsulfuration pathway (TSP) when food consumption is low or if the diet is predominantly plant based. The decline of taurine was proposed as the driver of aging through an undefined mechanism. Here, we found that mild food restriction in humans for one year that resulted in 14% reduction of calorie intake elevated the hypotaurine and taurine concentration in adipose tissue. Therefore, we investigated whether elevated taurine mimics caloric-restriction's beneficial effects on inflammation, a key mechanism of aging. Interestingly, aging increased the circulating and tissue concentrations of taurine suggesting that elevated taurine may serve as a hormetic stress response metabolite that regulates mechanism of age-related inflammation. The elevated taurine protected mice against mortality from sepsis and inhibited inflammasome-driven inflammation and gasdermin-D (GSDMD) mediated pyroptosis. Mechanistically, 'danger signals' including hypotonicity that activate NLRP3-inflammasome, caused upstream taurine efflux from macrophages, which triggered potassium (K + ) release and downstream canonical NLRP3 inflammasome assembly, caspase-1 activation, GSDMD cleavage and IL-1β and IL-18 secretion that was reversed by taurine restoration. Notably, taurine does not efflux from GSDMD pore and inhibited IL-1β from macrophages independently of known transporters SLC6A6 and SLC36A1. Increased taurine in old mice promotes healthspan by inducing anti-inflammatory pathways previously linked to youthfulness. These findings demonstrate that taurine is an upstream metabolic sensor of cellular perturbations that control NLRP3 inflammasome and lowers age-related inflammation.
    DOI:  https://doi.org/10.1101/2025.05.27.656381
  6. bioRxiv. 2025 Jun 04. pii: 2025.06.02.657436. [Epub ahead of print]
    PDE10A Inhibition Disrupts Lipid Droplet Formation and Sensitizes Macrophages to Ferroptosis after LPS treatment.
    Bradford C Berk, Jinmin Zhang, Chia George Hsu.
      Ferroptosis, an iron-dependent form of cell death, plays a key role in various diseases, but its impact on immune cells, particularly macrophages, remains unclear. This study explores how macrophage activation influences susceptibility to ferroptosis, focusing on lipopolysaccharide (LPS) and other inflammatory signals. We found that LPS priming enhanced resistance to ferroptosis in bone marrow-derived macrophages (BMDMs), as shown by reduced morphological changes, lower LDH release, and diminished cell death in real-time assays. Similar effects were observed with Zymosan A and TNF-α. Importantly, LPS-induced ferroptosis resistance was independent of stress response pathways like Nrf2 signaling. Instead, lipid droplet accumulation, driven by LPS, was central to this resistance. PDE10A inhibition reversed LPS-induced ferroptosis and reduced lipid droplet formation. LPS did not confer similar resistance in non-macrophage cell types, underscoring the macrophage-specific nature of this response. These findings highlight potential therapeutic targets for inflammatory diseases.
    DOI:  https://doi.org/10.1101/2025.06.02.657436
  7. Eur J Med Chem. 2025 May 29. pii: S0223-5234(25)00561-6. [Epub ahead of print]296 117796
    Discovery and structure-activity relationship studies of 3-pyridazinesulfonyl derivatives as a new class of inhibitors against NLRP3 inflammasome-dependent pyroptosis.
    Jinshan Nan, Shanmian Ji, Nenghua Zhou, Yan Jiao, Yun Zhang, Shengyong Yang, Mingli Xiang, Linli Li.
      Inflammatory programmed cell death mediated by NLRP3 inflammasome activation is one of the most representative forms of pyroptosis, involving multiple autoinflammatory diseases. In this investigation, we report the discovery of 3-pyridazinesulfonyl derivatives as a new class of inhibitors against NLRP3 inflammasome-dependent pyroptosis. We initially performed a phenotypic screening against NLRP3-dependent pyroptosis and discovered compound 1 (Hit-1), which showed moderate anti-pyroptotic activity (EC50 = 10.977 ± 2.122 μM). Further structure-activity relationship (SAR) studies resulted in a novel potent compound 32 (N102), which exhibited an EC50 of 0.029 ± 0.010 μM against cell pyroptosis induced by nigericin. N102 displayed remarkable inhibitory activity against NLRP3-dependent activation of caspase-1 and the release of IL-1β in human THP-1 cell-derived macrophages. Mechanistically, N102 disturbed the interaction of NLRP3 with the adaptor protein ASC and inhibited ASC oligomerization. Moreover, N102 possesses favorable HLM stability (T1/2 > 120 min), low CYP3A4 inhibition (IC50 > 10 μM) and good permeability (Papp = 9.063 × 10-5 cm s-1). Overall, we discovered a new potent small molecular inhibitor against NLRP3 inflammasome-dependent pyroptosis with potent cellular activity, favorable human-derived metabolic stability and permeability in vitro, which could be a good lead compound and deserves further in-depth studies.
    Keywords:  ASC oligomerization; NLRP3 inflammasome; Pyridazinesulfonyl derivative; Pyroptosis inhibitor
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117796
  8. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2426660122
    PARP12-mediated mono-ADP-ribosylation as a checkpoint for necroptosis and apoptosis.
    Xin Huang, Fangxia Li, Lin Liu, Yanxia Li, Mengmeng Zhang, Guoming Ma, Ying Gao, Bing Shan, Xiaozhen Liang, Junying Yuan, Heling Pan.
      Necroptosis and apoptosis are two alternatively regulated cell death pathways. Activation of RIPK1 upon engagement of TNFR1 by TNFα may promote necroptosis by interacting with RIPK3 or apoptosis by activating caspases. RIPK1 is extensively regulated by a variety of dynamic posttranslational modifications which control its kinase activity and formation of downstream complexes to mediate necroptosis and apoptosis. Here, we investigate the functional significance and mechanism by which PARP12, a mono-ADP-ribosyltransferase, interacts with RIPK1 and RIPK3 in cells stimulated by IFNγ and TNFα. We show that PARP12 catalyzes the mono-ADP-ribosylation (MARylation) of RIPK1 in both the intermediate domain and the kinase domain, as well as the MARylation of RIPK3. PARP12 deficiency reduces necroptosis by inhibiting the activation of RIPK1 kinase and its interaction with RIPK3, as well as sensitizes to apoptosis by promoting the binding of RIPK1 with caspase-8. Thus, upon induction by IFNs, PARP12 may function as a cellular checkpoint that controls RIPK1 to promote necroptosis and inhibit apoptosis. Importantly, while PARP12 is a known interferon-stimulated gene (ISG), PARP12 deficiency promotes the expression of a subset of ISGs and confers protection against influenza A virus-induced mortality in mice. Our study demonstrates that PARP12 is an important modulator of cellular antiviral response.
    Keywords:  MARylation; Parp12; RIPK1; influenza A virus; interferon
    DOI:  https://doi.org/10.1073/pnas.2426660122
  9. Cell Death Dis. 2025 Jun 06. 16(1): 440
    Gasdermin E deficiency limits inflammation and lung damage during influenza virus infection.
    Sarah Rosli, Rebecca L Ambrose, Christopher M Harpur, Maggie Lam, Christopher Hodges, Kristian T Barry, Alison C West, Ashley Mansell, Kate E Lawlor, Michelle D Tate.
      Severe influenza A virus (IAV) infections are associated with hyperinflammation and significant lung damage. Gasdermin E (GSDME) mediates pyroptosis, a lytic and inflammatory type of cell death. Cleavage of GSDME by caspase-3 releases the active N-terminal domain, which subsequently forms transmembrane pores, leading to cell lysis and death. In this study, we investigated a role for GSDME in severe influenza. Infection of human bronchial epithelial cells revealed that IAV induces GSDME cleavage and activation, with the magnitude and kinetics of GSDME activation differing between IAV strains. Caspase-3-mediated GSDME activation preceded and overwhelmed gasdermin D (GSDMD) activation. siRNA silencing in vitro confirmed both gasdermins are active in human bronchial epithelial cells and cooperate to drive IAV responses. IAV infection of mice promoted GSDME cleavage in E-cadherin+ epithelial cells in vivo at day 3. Mice deficient in GSDME (Gsdme-/-) showed improved survival and greater influenza disease resistance compared to their wildtype littermate controls. Gsdme-/- mice exhibited reduced neutrophil infiltration and levels of cytokines IL-6 and IL-1β in the airways and IL-6, TNF, and IFNγ in the serum. This was accompanied by reduced viral loads, lung pathology, and epithelial cell death. Together, these findings demonstrate a pivotal role for GSDME in severe influenza pathogenesis.
    DOI:  https://doi.org/10.1038/s41419-025-07748-0
  10. Cell Rep. 2025 Jun 07. pii: S2211-1247(25)00575-3. [Epub ahead of print]44(6): 115804
    Cell death and cancer: Metabolic interconnections.
    Destiny Dalseno, Nikolai Gajic, Lyndsey Flanagan, Stephen W G Tait.
      Recent findings in the cell death field have transformed our understanding of the interplay between metabolism and cell death in the context of cancer. In this review, we discuss the relationships between metabolism and the cell death pathways of apoptosis, necroptosis, pyroptosis, and ferroptosis, with a particular focus on recent advancements. We will also explore the regulation of metabolism by the BCL-2 family and the participation of oncometabolites in the regulation of cell death. Finally, we examine the emerging links between cell death signaling and cellular persistence. As we highlight in this review, the intersection of metabolic and cell death pathways has implications for cancer cell survival, treatment resistance, and the tumor microenvironment.
    Keywords:  BCL-2; CP: Cancer; CP: Metabolism; apoptosis; cancer; cell death; ferroptosis; metabolism; necroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115804
  11. Nature. 2025 Jun 09.
    NINJ1 regulates plasma membrane fragility under mechanical strain.
    Yunfeng Zhu, Fang Xiao, Yiling Wang, Yufang Wang, Jialin Li, Dongmei Zhong, Zhilei Huang, Miao Yu, Zhirong Wang, Joshua Barbara, Christopher Plunkett, Mengxue Zeng, Yiyan Song, Tian Tan, Ruibin Zhang, Kezhen Xu, Zhongxing Wang, Changjie Cai, Xiangdong Guan, Scott Hammack, Liang Zhang, Zheng Shi, Fu-Li Xiang, Feng Shao, Jie Xu.
      Plasma membrane integrity is vital for nearly all aspects of cell functioning1. Mechanical forces can cause plasma membrane damage2, but it is not known whether there are large molecules that regulate plasma membrane integrity under mechanical strain. Here we constructed a 384-well cellular stretch system that delivers precise, reproducible strain to cultured cells. Using the system, we screened 10,843 siRNAs targeting 2,726 multi-pass transmembrane proteins for strain-induced membrane permeability changes. The screen identified NINJ1, a protein recently proposed to regulate pyroptosis and other lytic cell death3,4, as the top hit. We demonstrate that NINJ1 is a critical regulator for mechanical strain-induced plasma membrane rupture (PMR), without the need of stimulating any cell death programs. NINJ1 level on the plasma membrane is inversely correlated to the amount of force required to rupture the membrane. In the pyroptosis context, NINJ1 on its own is not sufficient to fully rupture the membrane, and additional mechanical force is required for full PMR. Our work establishes that NINJ1 functions as a bona fide determinant of membrane biomechanical properties. Our study also suggests that PMR across tissues of distinct mechanical microenvironments is subjected to fine tuning by differences in NINJ1 expression and external forces.
    DOI:  https://doi.org/10.1038/s41586-025-09222-5
  12. Curr Biol. 2025 Jun 09. pii: S0960-9822(25)00441-5. [Epub ahead of print]35(11): R406-R409
    Cell death: Dynamics and compartmentalization of NADH and FSP1 in ferroptosis.
    Amalia H Megarioti, Kirandeep K Deol, James A Olzmann.
      A new study identifies the aldehyde dehydrogenase ALDH7A1 as a key regulator of ferroptosis. ALDH7A1 generates a pool of membrane-associated NADH, which is used by ferroptosis suppressor protein 1 to recycle the lipid antioxidant coenzyme Q10 and suppress ferroptosis.
    DOI:  https://doi.org/10.1016/j.cub.2025.04.012
  13. iScience. 2025 Jun 20. 28(6): 112587
    JNK signaling coordinates epithelial cell turnover through exocytosis in Drosophila ribosomal protein mutants.
    Nanami Akai, Yoshimasa Yagi, Tatsushi Igaki, Shizue Ohsawa.
      Robust tissue growth is orchestrated by the precise coordination of cell death and cell proliferation. In the developing wing pouches of Drosophila Minute/+ animals, both cell death and compensatory cell proliferation are increased, thereby contributing to robust growth of mutant tissue. Here, we show that JNK-mediated elevation of exocytosis in dying cells is crucial for triggering cell turnover in M/+ wing morphogenesis. Mechanistically, elevated JNK signaling in dying cells upregulates exocytosis-related genes and Wingless (Wg), leading to enhanced Wg secretion. Notably, increased exocytosis promotes caspase activation via an exocytosis-Dronc amplification loop, sustaining apoptotic signaling while reinforcing Wg secretion through Dronc activation. Furthermore, this exocytosis-mediated Wg secretion and apoptotic feedback loop universally occurs downstream of JNK signaling, regardless of the genetic background. Overall, our findings provide mechanistic insights into robust tissue growth through the orchestration of cell turnover, primarily via JNK-mediated exocytosis during Drosophila Minute/+ wing morphogenesis.
    Keywords:  Cell biology; Developmental biology; Functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112587
  14. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2500711122
    The CARD14sh-BCL10-MALT1 complex regulates MAVS-mediated antiviral response in keratinocytes.
    Lucrezia Zerillo, Tiziana Zotti, Angelapia Tutela, Jessica Raffaella Madera, Gabriella Grasso, Pasquale Vito, Romania Stilo.
      The Mitochondrial Antiviral Signaling Protein (MAVS) is a key adaptor in antiviral immunity, mediating type I interferon responses downstream of RIG1 and TLR3. While MAVS regulation is essential for antiviral defense, its modulation in keratinocytes is poorly understood. Here, we examine the role of the CARD14-BCL10-MALT1 (CBM) complex, a skin-specific signaling module, in controlling MAVS-dependent antiviral responses. We identify CARD14short as a dual regulator that activates NF-κB while inhibiting IRF3 signaling. Psoriasis-associated CARD14 mutations are less efficient in restricting IRF3 activation and cytokine production upon Poly (I:C) stimulation, highlighting a potential mechanism in psoriasis pathogenesis. BCL10 is essential for MAVS-induced IRF3 activation, while MALT1 limits IRF3 signaling by promoting MAVS cleavage, K48-linked ubiquitination, and proteasomal degradation. Genetic and chemical inhibition of MALT1 enhances IRF3 activation and type I IFN expression. These findings reveal a MAVS-CBM regulatory network linking innate immunity to epithelial homeostasis.
    Keywords:  antiviral response; innate immunity; psoriasis; skin homeostasis
    DOI:  https://doi.org/10.1073/pnas.2500711122
  15. BMC Biol. 2025 Jun 06. 23(1): 158
    Ferroptosis-related LncRNAs in diseases.
    Wu Zhou, Jean Paul Thiery.
      Ferroptosis is a form of regulated cell death (RCD) caused by the accumulation of intracellular iron and lipids and is involved in many pathological processes, including neurodegenerative and cardiovascular diseases, and cancer. Long non-coding RNAs (lncRNAs), RNA molecules exceeding 200 nt in length that do not possess protein coding function can interfere with ferroptosis by binding ferroptosis-related miRNAs or proteins. Recently, ferroptosis-related lncRNAs (FRlncRNAs) have been identified in cancer and non-malignant disease models, including inprediction of drug resistance, intra-tumoral immune infiltration, metabolic reprogramming and mutation landscape. Here, we review FRlncRNAs in cancer and non-malignant diseases, from prognosis to treatment.
    Keywords:  Cancer; Ferroptosis; LncRNAs; Non-malignant diseases
    DOI:  https://doi.org/10.1186/s12915-025-02268-x
  16. Cell Death Discov. 2025 Jun 10. 11(1): 271
    Hypoxia drives progression of multiple sclerosis by enhancing the inflammasome activation in macrophages with Porphyromonas gingivalis infection.
    Tokuju Okano, Hiroshi Ashida, Masayuki Tsukasaki, Tamako Iida, Masahiro Yamamoto, Hiroshi Takayanagi, Takeharu Sakamoto, Toshihiko Suzuki.
      Porphyromonas gingivalis (Pg), a gram-negative anaerobic bacterium, is a leading pathogen causing periodontitis. It secretes several virulence factors, including gingipains, lipopolysaccharides (LPS), and outer membrane vesicles (OMVs), which can trigger the release of inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor alpha (TNFα), and IL-6 through inflammasome activation and Toll-like receptor (TLR) signaling. We demonstrated that Pg infection under hypoxic conditions enhances NLRP3 inflammasome activation in macrophages. Additionally, we observed that toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-mediated hypoxia-inducible factor 1 alpha (HIF-1α) regulation exacerbates inflammasome activation under hypoxia. Notably, HIF-1α deficiency in myeloid cells reversed neurological symptoms and reduced IL-1β and IL-17 production in a mouse model of multiple sclerosis with Pg infection. Our findings indicated that hypoxia modulates inflammasome activation in response to periodontitis-related bacterial infections, contributing to the progression of autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41420-025-02548-z
  17. J Virol. 2025 Jun 12. e0187624
    GSDMD and GSDME exhibit distinct roles in enteric coronavirus PDCoV-induced pyroptosis and inflammatory responses.
    Chenyu Li, Yuting Shi, Chunying Xie, Kaiqi Duan, Tong Ding, Xiangfei Xu, Liurong Fang, Yanrong Zhou, Shaobo Xiao.
      Porcine deltacoronavirus (PDCoV), an emerging enteric coronavirus with zoonotic potential, typically causes intestinal villous epithelial cell damage with inflammation. Pyroptosis is a recently identified inflammatory form of programmed cell death that has been found to be associated with the pathogenesis of many viruses. However, the effects of PDCoV infection on pyroptosis and the role of pyroptosis in its pathogenesis remain unclear. In this study, we report that PDCoV infection triggers pyroptosis, as demonstrated in porcine ileum epithelial cell lines and intestinal tissues of PDCoV-infected piglets. Although both gasdermin D (GSDMD)- and gasdermin E (GSDME)-mediated pyroptosis were observed during PDCoV infection, GSDME dominated PDCoV-induced pyroptosis and subsequent inflammatory responses. More differently, GSDMD, rather than GSDME, exhibited potent anti-PDCoV activity; however, PDCoV-encoded nonstructural protein 5, a 3C-like protease, cleaved GSDMD, but not GSDME, to abolish the antiviral and pyroptotic functions of GSDMD. Our study elucidates the distinct roles of GSDMD and GSDME in PDCoV-induced pyroptosis and inflammatory responses, providing new insight into the pathogenesis of PDCoV and the potential for anti-PDCoV drug development.IMPORTANCEPyroptosis is a type of programmed cell death mediated by various gasdermins (GSDMs). While previous research has primarily focused on the role of GSDMD in pyroptosis, our study demonstrates that GSDME plays a dominant role in pyroptosis and the concomitant inflammatory responses induced by porcine deltacoronavirus (PDCoV), a newly identified enteric coronavirus with the potential to infect humans. The cleavage of GSDMD by PDCoV 3C-like protease may account for the diminished functionality of GSDMD in PDCoV-induced pyroptosis, which simultaneously disrupts its antiviral potential against PDCoV. These findings reveal the intricate interplay between PDCoV, GSDMD, and GSDME, accelerating the elucidation of PDCoV pathogenicity.
    Keywords:  3C-like protease (3CLpro); gasdermin D; gasdermin E; inflammatory response; porcine deltacoronavirus (PDCoV)
    DOI:  https://doi.org/10.1128/jvi.01876-24
  18. Cancer Immunol Immunother. 2025 Jun 07. 74(8): 238
    NLRP3 activation promotes cGAS/STING signaling and antitumor immunity by colorectal cancer cells.
    Courtney Mowat, Daniel Schiller, Kristi Baker.
       INTRODUCTION: Colorectal cancer (CRC) is a highly prevalent and deadly disease that is largely refractory to immunotherapy. The only CRC subset that responds to these therapies is characterized by prevalent microsatellite instability (MSI), extensive  CD8+ T cell infiltration and high expression of innate immune signaling pathways. Endogenous activation of the cGAS/STING pathway is essential for this CD8+ T cell antitumor response in MSI CRCs, suggesting that activating it in other CRCs could boost immunotherapy response rates. In contrast, activation of the NLRP3 inflammasome is typically associated with tumor-promoting inflammation although this has primarily been studied in immune cells.
    METHODS: We used a mixture of flow cytometry, activation assays, in vivo orthotopic models and patient-derived organoids to investigate the effect of NLRP3 activation in CRC cells on cGAS/STING-mediated antitumor immunity.
    RESULTS: Our results show that activation of the NLRP3 inflammasome specifically in CRC cells boosts cGAS/STING signaling in both MSI and non-MSI CRCs and that dual stimulation increases CD8+ T cell-mediated antitumor immunity. The ability of NLRP3 to enhance cGAS/STING signaling was specific and did not occur with activation of other innate immune pathways such as AIM2 or TLRs. Enhancement of cGAS/STING signaling by NLRP3 proceeded via a positive feedback loop that was inflammasome-independent and required early crosstalk between the signaling mediators and regulation of their gene expression.
    CONCLUSIONS: Activation of NLRP3 specifically in CRC cells could be a promising strategy to boost antitumor immunity in otherwise immunotherapy resistant CRCs.
    Keywords:  Antitumor immunity; Colorectal cancer; Microsatellite instability (MSI); NLRP3 inflammasome; cGAS/STING
    DOI:  https://doi.org/10.1007/s00262-025-04088-y
  19. Front Immunol. 2025 ;16 1546986
    Macrophage pyroptosis mediates hyperoxia-induced inflammatory lung injury in neonates.
    Zikun Tu, Haiyan Guo, Yajing Gao, Wenfeng Xiao, Xueru Xie, Hongmiao Yu, Qiuyan Liang, Yufeng Zhou.
       Background: Hyperoxia plays a key role in the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants. This study aimed to investigate the role of NLRP3/caspase-1/gasdermin D (GSDMD)-mediated pyroptosis in hyperoxia-induced lung injury in neonatal mice and to evaluate the potential protective effects of the caspase-1 inhibitor VX-765 on alveolar and vascular development in hyperoxia-exposed lungs.
    Materials and methods: C57/BL6 mouse pups were randomized on postnatal Day 4 (PN4) to receive daily intraperitoneal injections of VX-765, an effective and selective caspase-1 inhibitor, or a vehicle during exposure to room air or hyperoxia (85% O2) for 10 days. Alveolarization was assessed by H&E staining. Pulmonary vascular development was detected by CD31 immunohistochemistry. The degree of fibrosis was analyzed by Masson staining. TUNEL and Ki67 immunofluorescence staining was performed to assess overall cell survival in lung tissue. Concentrations of IL-1β was detected by ELISA in lung homogenates. The expressions of pyroptosis-associated proteins, NLRP3, Caspase-1 p20, N-GSDMD and mature IL-1β were evaluated by Western blot. Immunofluorescence colocalization of F4/80 with NLRP3/Caspase-1/IL-1β was performed. CD68 and AQP5 protein expression was analyzed by immunohistochemistry.
    Results: Hyperoxia activated the NLRP3 inflammasome, increased the production of mature IL-1β, and upregulated the expression of N-GSDMD, the active form of GSDMD that is responsible for the programmed cell death mechanism of pyroptosis in lung tissue. Importantly, VX-765 decreased NLRP3, IL-1β activation, and N-GSDMD expression and improved alveolar and vascular development by inhibiting pyroptosis of macrophages in hyperoxia-exposed lungs. Moreover, VX-765 also promoted cell proliferation and AT1 survival in the hyperoxia-exposed lung.
    Conclusion: NLRP3/Caspase-1/GSDMD-mediated pyroptosis plays a critical role in hyperoxia-induced neonatal lung injury, and targeting this pathway may be beneficial for the prevention of lung injury in preterm infants.
    Keywords:  VX-765; bronchopulmonary dysplasia (BPD); gasdermin D (GSDMD); macrophage; pyroptosis
    DOI:  https://doi.org/10.3389/fimmu.2025.1546986
  20. Eur J Immunol. 2025 Jun;55(6): e51176
    mTOR Modulates NLRP3 Inflammasome Activation via Nuclear Translocation and STAT1 Inhibition.
    Alvaro González-Dominguez, Shuling Zhang, Daniel Boy-Ruiz, Daniel Connors, Raquel de la Varga-Martínez, Beverly A Mock, Mario D Cordero.
      The NLRP3 inflammasome has emerged as an unexpected sensor of metabolic danger and stress. Their enhanced activation has been implicated in the development of major diseases such as gout, Type 2 diabetes, obesity, cancer, and neurodegenerative and cardiovascular diseases. In this study, we showed that mammalian target of rapamycin (mTOR) regulates NLRP3 inflammasome activation in the nucleus of macrophages. mTOR binds to NLRP3 under basal conditions, and this binding is reduced after lipopolysaccharides (LPS) or LPS + adenosine triphosphate (ATP) treatment. Furthermore, rapamycin-induced downregulation of mTOR expression has an inhibitory effect on NLRP3 inflammasome activation. mTOR knockdown (KD) mice exhibit reduced protein levels of inflammasome components, and their macrophages fail to activate the NLRP3 inflammasome after LPS + ATP treatment. From a mechanistic point of view, LPS + ATP treatment induced the nuclear translocation of mTOR, leading to enhanced NLRP3 inflammasome activation. However, the mTOR inhibition by rapamycin treatment increased phosphorylation of STAT1 which repressed NLRP3 activation. When rapamycin was combined with the STAT1 inhibitor fludarabine, NLRP3 inflammasome activity was restored. Taken together, these findings suggest a role for mTOR in NLRP3 regulation and identify a potential therapeutic option for controlling inflammasome activation.
    DOI:  https://doi.org/10.1002/eji.202451176
  21. bioRxiv. 2025 May 30. pii: 2025.05.27.656501. [Epub ahead of print]
    A caspase-1-cathepsin AND-gate probe for selective imaging of inflammasome activation.
    Shiyu Chen, Una Goncin, Jiyun Zhu, Shih-Po Su, Traci Ann Czyzyk, Corin O Miller, Raana Kashfi Sadabad, Matthew Bogyo.
      Caspase-1 is a key mediator of the inflammasome pathway, which is associated with several inflammatory disorders including obesity, diabetes mellitus (DM), cardiovascular diseases (CVDs), cancers and chronic respiratory diseases. Although substrate-based probes can be used to visualize the activity of caspase-1, none are selective enough for use as imaging agents. Here, we report the design and synthesis of a AND-gate substrate probe ( Cas1-Cat-Cy7 ) that requires processing by both caspase-1 and cathepsins to produce a signal. Because both enzymes are only found together and active at the site of inflammasome activation, the resulting probe can be used to image caspase-1 mediated inflammation. We demonstrate that the probe produces selective signals in ex vivo biochemical and cellular assays and in a mouse model of acute inflammation.
    DOI:  https://doi.org/10.1101/2025.05.27.656501
  22. Nature. 2025 Jun 11.
    SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity.
    Kristen C Witt, Adam Dziulko, Joohyun An, Filip Pekovic, Arthur Xiuyuan Cheng, Grace Y Liu, Ophelia Vosshall Lee, David J Turner, Azra Lari, Moritz M Gaidt, Roberto Chavez, Stefan A Fattinger, Preethy Abraham, Harmandeep Dhaliwal, Angus Y Lee, Dmitri I Kotov, Laurent Coscoy, Britt A Glaunsinger, Eugene Valkov, Edward B Chuong, Russell E Vance.
      Type I interferons are essential for antiviral immunity1 but must be tightly regulated2. The conserved transcriptional repressor SP140 inhibits interferon-β (Ifnb1) expression through an unknown mechanism3,4. Here we report that SP140 does not directly repress Ifnb1 transcription. Instead, SP140 negatively regulates Ifnb1 mRNA stability by directly repressing the expression of a previously uncharacterized regulator that we call RESIST (regulated stimulator of interferon via stabilization of transcript; previously annotated as annexin 2 receptor). RESIST promotes Ifnb1 mRNA stability by counteracting Ifnb1 mRNA destabilization mediated by the tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex. SP140 localizes within punctate structures called nuclear bodies that have important roles in silencing DNA-virus gene expression in the nucleus3. Consistent with this observation, we find that SP140 inhibits replication of the gammaherpesvirus MHV68. The antiviral activity of SP140 is independent of its ability to regulate Ifnb1. Our results establish dual antiviral and interferon regulatory functions for SP140. We propose that SP140 and RESIST participate in antiviral effector-triggered immunity5,6.
    DOI:  https://doi.org/10.1038/s41586-025-09152-2
  23. bioRxiv. 2025 May 27. pii: 2025.05.27.654580. [Epub ahead of print]
    Myeloid-specific TFAM deficiency drives mitochondrial DNA stress and exacerbates allergic airway inflammation.
    Jackie Nguyen, Courtney Van, Manjula Karpurapu, Jiyoung Kim, Tae Jin Lee, Ji Young Yoo, Navjot Pabla, John W Christman, Sangwoon Chung.
      Asthma is the most prevalent chronic inflammatory lung disease in adolescents and young adults, characterized by persistent airway inflammation and remodeling. Increasing evidence indicates that activated lung macrophages play a significant role in the initiation, intensity, progression, and resolution of allergic airway inflammation. However, the underlying mechanisms regulating macrophage-mediated inflammation in asthma remain incompletely understood. Our previous work revealed increased mitochondrial DNA (mtDNA) depletion and mitochondrial damages in the lungs of asthmatic mice, implicating mitochondrial dysfunction in disease pathogenesis. Given that mitochondrial transcription factor A (TFAM) is essential for mtDNA maintenance and integrity, we hypothesized that TFAM has a fundamental role in regulating mtDNA stress and downstream inflammtroy response in asthma. Using myeloid-specific TFAM knockout (TFAM fl/fl LysMcre, TFAM KO) mice subjected to allergens sensitization and challenge, we observed pronounced mitochondrial dysfunction and accentuated asthmatic inflammation. This was accompanied by elevated expression of asthma-associated mediators, including il-13, muc5a/c, muc5b, and ccl17. In addition, TFAM deficiency was associated with increased eosinophilia and and cytosolic mtDNA release, contributing to exacerbated airway pathology. Together, we have identified a critical role of TFAM in myeloid cells that contributes to asthmatic airway inflammation. These results suggest that therapeutic restoration of TFAM function may offer a novel strategy to mitigate mitochondrial stress, reduce airway inflammation, and improve outcomes in patients with moderate to severe asthma.
    DOI:  https://doi.org/10.1101/2025.05.27.654580
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒15 at 12:29.